Implants of polymer-encapsulated genetically modified cells releasing glial cell line-derived neurotrophic factor improve survival, growth, and function of fetal dopaminergic grafts.
Neural transplantation as an experimental therapy for Parkinsonian patients has been shown to be effective in several clinical trials. Further benefit, however, may be expected if the grafting is combined with a treatment of neurotrophic factors thus improving the survival and growth of grafted embryonic dopaminergic neurons. Continuous trophic support may be needed and therefore requires the long-term delivery of neurotrophic factors to the brain. We demonstrate here that the implantation of polymer-encapsulated cells genetically engineered to continuously secrete glial cell line-derived neurotrophic factor to the adult rat striatum improves dopaminergic graft survival and function. Near complete compensation of 6-hydroxydopamine-induced rotation was already achieved within 3 weeks postgrafting in rats that received glial cell line-derived neurotrophic factor-releasing capsules in addition to dopaminergic cell grafts of cultured tissue. Rats without trophic factor supply showed only little recovery at the same time point and sham grafted rats showed no recovery. The number of tyrosine hydroxylase-immunoreactive cells per graft was increased 2.6-fold in the presence of glial cell line-derived neurotrophic factor 6 weeks postgrafting. Similarly, tyrosine hydroxylase-immunoreactive fibers around the graft were increased by 53%. Moreover, these fibers showed a preferential growth towards the trophic factor-releasing capsule. Taken together, these results provide evidence that encapsulated genetically engineered cells are an effective means of long-term trophic factor supply into the adult rat brain and that the delivery of glial cell line-derived neurotrophic factor can sustain dopaminergic graft function and survival.
Sautter
J
J
Department of Neurosurgery, Inselspital, University of Bern, Switzerland.
Tseng
J L
JL
Braguglia
D
D
Aebischer
P
P
Spenger
C
C
Seiler
R W
RW
Widmer
H R
HR
Zurn
A D
AD
D000818:Animals; D002214:Capsules; D002460:Cell Line / Q000378:metabolism; D003342:Corpus Striatum / Q000601:surgery*; D006224:Cricetinae; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D016332:Fetal Tissue Transplantation; D005818:Genetic Engineering; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006085:Graft Survival / Q000502:physiology; D008636:Mesencephalon / Q000196:embryology* / Q000378:metabolism* / Q000503:physiopathology; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D009474:Neurons / Q000201:enzymology; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D011108:Polymers; D019736:Prostheses and Implants; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002214:Capsules; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011108:Polymers; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine